In approximately 30% of epileptic patients, seizures are not controlled by currently available therapeutic agents. Even though a number of new chemical entities have entered the marketplace, therapy resistant seizures remain. This project is innovative in that its goals are to create and test an entirely new set of small molecules with the prospect that lead compounds will exhibit protection against seizures in animal models and have reduced toxicity. Initial studies, conducted in the laboratory of Dr. Max Baker at the University of Iowa, showed that substitution at the para position of propofol, a commonly used sedative, yielded a compound having reduced anesthetic or sedative effects while maintaining anti-convulsant properties in the 6 Hz (32 mA) mouse model conducted at the Anti-convulsant Screening Program (ASP), NINDS. Propofol and this novel analog, 2,6-diisopropyl-4-(1-hydroxy-2,2,2-trifluoroethyl)phenol (MB003), both exhibit lower ED50s than many other anti-convulsant drugs including valproic acid, felbamate, carbamazepine, phenytoin, and ethosuximide. Therefore, the substantially reduced sedative activity for MB003 compared to propofol, allows for the possibility of wider use of this compound for seizure treatment. Currently, the structural elements of MB003 required for anti-seizure activity are not well understood, and so a concise and directed medicinal chemistry effort to deconvolute the structure-activity relationship is required in order to move this opportunity toward commercialization. This Proposal consists of two Aims: 1) create and execute a rational medicinal chemistry plan exploring structure-activity relationships around the propofol pharmacophore, and 2) test these compounds at the ASP, NINDS in models of seizures and sedation. The primary objective of this proposal is to identify a lead drug candidate with strong anti- convulsant efficacy with an acceptable side-effect profile. The ultimate goal of this research program (SBIR phase I, II and III) is to create a new oral anti-convulsant for chronic and prophylactic use. Tansna Therapeutic Inc. was co-founded by the inventor of these compounds, Dr. Baker, to commercialize this technology by developing para-substituted analogs of propofol with good anti- convulsant properties. SARmont, LLC, is a drug discovery and design company, led by Dr. John Talley, the lead inventor of Celebrex(R) and 7 other NCEs that have made it to the marketplace. Tansna will contract SARmont to provide medicinal chemistry services, specifically in molecular design and structure-activity relationship analysis. Tansna and SARmont will collaborate on compound synthesis, and in vivo testing will occur at the NINDS. Success in this Proposal will lead to the submission of a Phase II grant focused on further medicinal chemistry optimization, more rigorous mammalian safety testing, and other pre-clinical studies required for IND submission. PUBLIC HEALTH RELEVANCE: Approximately 30% of epileptic patients are resistant to currently available therapeutic agents. Novel and effective anti-convulsants are needed to address this unmet medical need. Propofol is a general anesthetic known to have good anti-convulsant properties;however use of propofol as an anti-seizure medicine is limited due to its potent anesthetic/sedative properties. The primary objective of this Proposal is to identify a lead drug candidate with strong anti-convulsant efficacy with an acceptable side-effect profile.